Experimental and Theoretical Investigation of the Synchronicity of Ambident Silyloxypyrone-Based (5 + 2) Cycloadditions.

The reaction pathway of silyloxypyrone-based (5 + 2) cycloadditions was determined to be extremely dependent on the nature of the dipolarophile. Neutral alkenes were the least reactive, whereas both electron-deficient and electron-rich dipolarophiles were more reactive, thus providing evidence for ambident oxidopyrylium intermediates. Qualitative rate studies, Hammett linear free energy relationships, and theoretical calculations combined to provide evidence for a spectrum of reactivity that passes through the borderlands of concerted and stepwise.

Synthesis of Polycyclic Ether-Benzopyrans and In Vitro Inhibitory Activity against Leishmania tarentolae.

Construction of a focused library of polycyclic ether-benzopyrans was undertaken in order to discover new therapeutic compounds that affect Leishmania growth and infectivity. This is especially of interest since there are few drug therapies for leishmaniasis that do not have serious drawbacks such high cost, side effects, and emerging drug resistance. The construction of these polycyclic ether-benzopyrans utilized an acetoxypyranone-alkene [5+2] cycloaddition and the Suzuki-Miyaura cross-coupling. The multi-gram quantity of the requisite aryl bromide was obtained followed by effective Pd-catalyzed coupling with boronic acid derivatives. Compounds were tested in vitro using the parasitic protozoan, Leishmania tarentolae. Effects of concentration, time, and exposure to light were evaluated. In addition, the effects on secreted acid phosphatase activity and nitric oxide production were investigated, since both have been implicated in parasite infectivity. The data presented herein are indicative of disruption of the Leishmania tarentolae and thus provide impetus for the development and testing of a more extensive library.

Investigation of Transfer Group, Tether Proximity, and Alkene Substitution for Intramolecular Silyloxypyrone-Based [5 + 2] Cycloadditions.

Systematic investigation of intramolecular silyloxypyrone-based [5 + 2] cycloadditions revealed three significant factors impacting conversion to cycloadduct: (1) the silyl transfer group has a substantial influence on the rate of reaction, and the robust t-butyldiphenylsilyl group was found to be more effective overall than the conventional t-butyldimethylsilyl group; (2) α,ß-unsaturated esters were generally more reactive than terminal olefins and afforded appreciable quantity of cycloadduct even at room temperature; and (3) the proximity of the tether to the silyl transfer group revealed a critical alignment trend between the pyrone and the alkene. Taken together, these investigations provided insight regarding the steric and electronic parameters that impact the scope and limitation of these reactions.